A R T I C L E
Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors
Jan Styczyński1●Gloria Tridello2●Linda Koster3●Simona Iacobelli4●Anja van Biezen3●Steffie van der Werf3● Małgorzata Mikulska5●Lidia Gil6●Catherine Cordonnier7●Per Ljungman 8●Diana Averbuch9●Simone Cesaro 2● Rafael de la Camara 10●Helen Baldomero11●Peter Bader12●Grzegorz Basak 13●Chiara Bonini14 ●
Rafael Duarte15●Carlo Dufour16●Jurgen Kuball17●Arjan Lankester18●Silvia Montoto19●Arnon Nagler20● John A. Snowden21●Nicolaus Kröger22●Mohamad Mohty23●Alois Gratwohl24●for the Infectious
Diseases Working Party EBMT
Received: 22 July 2018 / Revised: 2 April 2019 / Accepted: 28 May 2019 / Published online: 27 August 2019
© The Author(s) 2019. This article is published with open access
Abstract
Information on incidence, and factors associated with mortality is a prerequisite to improve outcome after hematopoietic stem cell transplantation (HSCT). Therefore, 55′668 deaths in 114′491 patients with HSCT (83.7% allogeneic) for leukemia were investigated in a landmark analysis for causes of death at day 30 (very early), day 100 (early), at 1 year (intermediate) and at 5 years (late). Mortality from all causes decreased from cohort 1 (1980–2001) to cohort 2 (2002–2015) in all post- transplant phases after autologous HSCT. After allogeneic HSCT, mortality from infections, GVHD, and toxicity decreased up to 1 year, increased at 5 years; deaths from relapse increased in all post-transplant phases. Infections of unknown origin were the main cause of infectious deaths. Lethal bacterial and fungal infections decreased from cohort 1 to cohort 2, not unknown or mixed infections. Infectious deaths were associated with patient-, disease-, donor type, stem cell source, center, and country- related factors. Their impact varied over the post-transplant phases. Transplant centres have successfully managed to reduce death after HSCT in the early and intermediate post-transplant phases, and have identified risk factors.
Late post-transplant care could be improved by focus on groups at risk and better identification of infections of “unknown origin”.
Introduction
Besides the risk of relapse, hematopoietic stem cell trans- plantation (HSCT) remains associated with significant early and late treatment related mortality (TRM). Infections, toxicity, and (after allogeneic HSCT only), graft-vs.-host disease (GVHD) are the main causes of death. An earlier EBMT (European Society for Blood and Marrow Trans- plantation) analysis of patients with good risk leukemia transplanted between 1980–2001 had shown a significant increase in the 5-year survival rate from the 1980ies to the
1990ies, primarily due to a marked reduction of infectious deaths [1]. Since then, HSCT has become established as a valuable treatment option. The number of transplants has substantially increased [2–4], indications for HSCT have broadened [5], and new technologies have been introduced [4,6–8]. It is estimated today that more than 1.4 million transplants have been performed so far worldwide; about 70′000 patients are now being treated annually with HSCT, half of them in Europe [3].
The improvement in outcome in the 1990ies has been confirmed by a single centre study for the years 1993–2007 in the United States. It showed a reduction of deaths from organ damage, infections, and severe acute GVHD [2]. No in depth large analysis has been conducted since. New antibiotics, new antifungal and antiviral agents have been introduced [9–14]. The large expansion of unrelated donor registries and the use of haploidentical transplants have given access to donors for many more patients [4]. The introduction of reduced-intensity conditioning transplants
* Jan Styczyński [email protected]
Extended author information available on the last page of the article.
Supplementary information The online version of this article (https://
doi.org/10.1038/s41409-019-0624-z) contains supplementary material, which is available to authorized users.
made HSCT accessible for elderly and frail patients [6].
Still, it remains unknown whether deaths from infections continued to decline since 2001. Furthermore, factors associated with death from infections, a prerequisite for further improvement, are largely unknown. We therefore designed the study to analyse the causes of deaths after HSCT over calendar year time, at specified post-transplant time phases, and searched for factors associated with it. We hypothesized that the key factors differ depending on the time phase after HSCT, both after allogeneic and autologous HSCT.
Patients and methods
Study designThis retrospective, observational study included all patients with HSCT from all donor types and stem cell sources for acute lymphoblastic leukemia (ALL), acute myeloid leu- kemia (AML) or chronic myeloid leukemia (CML) between 1980 and 2015, reported by 588 centers from 51 countries to the EBMT database. This patient selection and the two time periods (cohort 1 from 1980–2001and cohort 2 from 2002–2015) were based on a previous study, but did include now all disease stages, not onlyfirst CR patients [1]. There were no exclusion criteria. All data collection was per- formed by the IDWP Data Office (Leiden) according to EBMT guidelines (http://www.ebmt.org/retrospective- studies).
The analysis followed a stepwise approach. First, the data cohort was set up: all transplants in the EBMT datafile from 1980 to 2015 were retrieved and assessed for com- pleteness as specified below. In the second step, this file with complete information was closed as of January 1st 2017, and recoded for the specific new grouping of donor type and centre and country specific economic parameters.
Data were verified, and the descriptive analysis was performed.
All EBMT teams are required to obtain patients’ consent for data transfer to EBMT and to have internal review board approval for their transplant programs. The data set was locked and anonymized. No centers were contacted for missing information. No additional ethics approval was mandated.
Study population
The study comprised a total number of 114′491 patients with HSCT, 95′789 (84%) allogeneic and 18′702 (16%) autologous, for AML (57.2%), ALL (25.4%), or CML (17.4%); of these 42′997 (37.6%) were in cohort 1, and 71′
494(62.4%) in cohort 2. There were 56.5% male, 43.5%
female patients with a median age of 37 years (0–84 years range) (Table1).
Working definitions
Death after transplant was categorized as previously defined [1,15] into death from relapse (RM, relapse mortality: any death after relapse) and death from causes other than relapse (GVHD, toxicity, infection, other and unknown causes).
Infectious deaths were analysed as total, and split by bac- terial, fungal, viral, parasitic, mixed, and unknown infections.
Disease stage was defined as early disease (CR1 in ALL and AML;first CP in CML) or late disease (all other: ≥CR2, progression, refractory/relapsed).
Donor type was analysed in 10 types as previously described: autologous, syngeneic, HLA-identical sibling donor HY-, HLA-identical sibling donor HY+, matched family donor HY-, matched family donor HY+, matched unrelated donor HY-, matched unrelated donor HY+, mis- matched unrelated donor, mismatched family donor (HY+ refers to a female donor for a male recipient; HY- to all other donor-recipient sex combinations) [16]. Matching was used as classified by the reporting team, at the time of first report.
Acute GVHD was graded according to previously pub- lished criteria [17]. Chronic GVHD was graded as limited or extensive.
Centre specific microeconomic and country specific macroeconomic factors were integrated as previously described [18]. Centre size was defined for each transplant by the number of transplants performed in the centre for the main disease of the patient in the year of the transplant (0–4, 5–19, 20+ transplants). Centre experience in years was defined by the number of years that the centre had per- formed transplants until the year of the transplant of the patient (0–4, 5–19, 20+ years of program). Country mac- roeconomic status was defined by gross national income (GNI/capita) in 2016: high income, upper middle income, lower middle income (source: www.worldbank.org). Geo- graphical regions were defined as: north-western eastern and southern (see Table 3A and Table 3B for details).
JACIE accreditation status (accredited, expired, withdrawn and not accredited) in 2016 was used.
Statistical analysis
The primary endpoint was to compute the cumulative incidence (CumInc) of overall post-transplant mortality in cohorts 1 and 2. The CumInc of death was reported at specified time phases after the transplant (very early: day +30, early: day +100, intermediate: +1 year and late: +5 years) in a landmark approach. Analysis at day +30
Table 1 Patients population
Year of last transplant Total p value
1980–2001 2002–2015
N % N % N %
42997 37.55 71494 62.45 114491 100.00
Sex
Male 24656 57.34 40038 56.00 64694 56.51 <0.0001
Female 18341 42.66 31456 44.00 49797 43.49
Age at last HSCT (years)
Median 33.1 41.0 37.4 <0.0001
Range 0.2–77.9 0.0–83.8 0.0–83.8
Mean (SD) 32.24 (15.04) 38.95 (18.14) 36.43 (17.35)
N obs 42972 71465 114437
Underlying disease
AML 20132 46.82 45386 63.48 65518 57.23 <0.0001
ALL 9431 21.93 19652 27.49 29083 25.40
CML 13434 31.24 6456 9.03 19890 17.37
Stage at last transplant
early 27495 63.95 43946 61.47 71441 62.40 <0.0001
late 15502 36.05 27548 38.53 43050 37.60
Type of HSCT
Allogeneic 31128 72.40 64661 90.44 95789 83.67 <0.0001
Autologous 11869 27.60 6833 9.56 18702 16.33
Stem cell source
BM 30218 70.28 15466 21.63 45684 39.90 <0.0001
PB 12442 28.94 53829 75.29 66271 57.88
CB 337 0.78 2199 3.08 2536 2.22
T-cell depletion
no 14097 62.24 30792 50.67 44889 53.81 <0.0001
yes in vivo, no ex vivo 2881 12.72 26488 43.59 29369 35.21
yes ex vivo, no in vivo 3201 14.13 1357 2.23 4558 5.46
yes in vivo+ ex vivo 2472 10.91 2129 3.50 4601 5.52
Conditioning regimen
standard 32708 96.38 45487 70.77 78195 79.62 <0.0001
reduced 1230 3.62 18788 29.23 20018 20.38
First HSCT
No 2906 6.76 6342 8.87 9248 8.08 <0.0001
Yes 40091 93.24 65152 91.13 105243 91.92
Geographic regions
north-west 26319 61.21 38629 54.03 64948 56.73 <0.0001
south 14470 33.65 25987 36.35 40457 35.34
east 2208 5.14 6878 9.62 9086 7.94
GNI per capita 2015a
High income 41424 96.34 63712 89.12 105136 91.83 <0.0001
Upper middle income 1565 3.64 7671 10.73 9236 8.07
Lower middle income 8 0.02 111 0.16 119 0.10
JACIE accreditation 2016
accredited 22935 53.34 36420 50.94 59355 51.84 <0.0001
expired 7827 18.20 8439 11.80 16266 14.21
withdrawn 279 0.65 369 0.52 648 0.57
not accredited 11956 27.81 26266 36.74 38222 33.38
Centre experienceb
0–4 6295 14.64 2236 3.13 8531 7.45 <0.0001
5–19 31026 72.16 29652 41.47 60678 53.00
20+ 5676 13.20 39606 55.40 45282 39.55
Centre sizec
0–4 14940 34.75 14965 20.93 29905 26.12 <0.0001
5–19 24345 56.62 37794 52.86 62139 54.27
20+ 3712 8.63 18735 26.20 22447 19.61
aAtlas methodology
bcalculated from ProMISE: number of years performing transplants until the year of transplant of the patient
ccalculated from ProMISE: number of transplants with the same disease and same year of transplant as the patient All the differences resulted statistically significant (p < 0.0001)
included all patients, the analyses at day+100, year +1, year +5 included patients alive at day +30, day +100, year+1, respectively.
Secondary endpoints were, as in the previous report [1], the CumInc of mortality due to relapse, GVHD, infection, other and unknown causes. GVHD was used as “any GVHD ever”, not separated by acute or chronic GVHD.
The cumulative incidence estimator was applied, with the Gray test being used to compare different groups. Differ- ences in CumInc rates without overlapping of the 95%CI’s were considered as significant.
The cause-specific Cox model was used to detect the factors related to the infection death for the four post- transplant phases. The death due to infection was con- sidered as event of interest and death due to other causes as competing event.
Factors integrated into the analysis were sex and age of the patients, main diagnosis (ALL or AML or CML), stage of the disease, donor/recipient sex matching (HY-vs HY+), type of donor (HLA-matched sibling vs other donor types), type of conditioning (RIC vs MAC), source of stem cells (PB vs BM vs CB), year and number of transplantation and presence or absence of in vivo and ex vivo T-cell depletion, and macro- and microeconomic center data as explained above. Factors with a p-value < 0.2 from the univariate analysis were included in the multivariate analysis. Factors with ap value of <0.05 were considered as significant.
Comparisons for categorical variables were done using the Fisher’s exact test or the χ2test. The proportional hazard assumption was verified using graphical methods: scaled Schoenfeld [19] residuals and graphical checks proposed by Klein-Moeschberger [20] were performed without finding evidence of relevant violations. All the analyses were per- formed using the statistical software SAS (SAS Institute Inc., Cary, NC, USA) version 9.4.
Results
Patient population and demographic changes over calendar time
There were significant differences in absolute numbers, in patients, disease and donor characteristics, as well as in transplant procedure techniques between the two cohorts.
Median age increased from 33.1 years to 41.0 years. The proportion and the absolute numbers of patients with AML and ALL increased, the ones of CML decreased. There were more allogeneic HSCT in the second cohort, more trans- plants with reduced intensity conditioning and more trans- plants with peripheral blood as stem cell source. Economic factors showed changes, with more transplants in the second cohort from eastern and lower income countries and within
non accredited centres; there was an increase in transplants in more experienced centres by patient volume and years of transplants (Table1).
Main causes of death and changes over post- transplant phase and calendar time
A total of the 55′668 patients were reported as having died, 52′448 thereof during the observation period (45.8% of all patients; 43′930 after allogeneic, 8′518 after autologous HSCT): 22′518 (42.9%) died from relapse, 8′361 (15.9%) from GvHD, 11′701 (22.3%) from infections, 8028 (15.3%) from other, and 1540 (2.9%) from unknown causes (Table 2A and Table 2B). There were major differences between allogeneic (Table 2A, S5) and autologous (Table 2B, S6) HSCT, regarding main causes of death, changes over post-transplant phases and changes over calendar year time (Figs.1–3, Fig. S1A). Main cause of death was relapse after both, allogeneic (38.7%) and autologous (64.5%), followed by infections (23.8% allogeneic; 14.8%
autologous), and GvHD (19.0% allogeneic only). After allogeneic HSCT, 15′418 (35.1%) of all deaths occurred during the first 100 days, 10′174 (23.0%) between 1 and 5 years after the transplant, in contrast to autologous HSCT with 1587 (18.6%) of deaths within the first 100 days and 2925 (34.3%) of deaths between 1 and 5 year post-transplant.
The changes in mortality from cohort 1 to cohort 2 dif- fered between allogeneic and autologous HSCT for the four post-transplant periods. In the landmark analysis, the cumulative incidence of overall mortality decreased from cohort 1 to cohort 2 at +30d (p < 0.001), at +100d (p <
0.001), and at +1y (p < 0.001), but increased at +5y (p <
0.01) (Fig. 1, Table 2A and Table 2B, Table S1A). After autologous HSCT, the cumulative incidence for overall mortality decreased in each of the four post-transplant phases for each cause of death, including relapse except for
“other” causes of death in very late phase (Table 2A and Table 2B, S1B). After allogeneic HSCT, mortality from GVHD, and other causes decreased in the very early, early, and intermediate phases, but increased in the late phase for GVHD and for other causes (Fig.2, Table2A and Table2B, S1C). Mortality from relapse increased in all post-transplant phases. As a result, overall mortality decreased in the very early (+d30; p < 0.0001) and early phase (+d100; p <
0.0001), but increased in the late phase (+5y: p < 0.0001) (Table 2A and Table2B, S1C).
Causes of infectious death and changes over post- transplant phase and calendar year time
A total of 11′941 patients died of infectious complications.
The majority of lethal infections (59.4%) were of unknown etiology, 14.7% were of bacterial, 10.6% of fungal, 9.2% of
Table2ACausesofdeathsin114′491patientswithleukemiaandHSCTbetween1980and2015,andcumulativeincidencesofdeathsdependingonpatientcohortandtimeperiodafter transplant.Patientsafterallo-HSCT TimeperiodCohortTotalatentryRelapseGvHDInfectionOthercausesUnknownTotal NDCumInc+CINDCumInc+CINDCumInc+CINDCumInc+CINDCumInc+CINDCumInc+CI 30days131128810.26**(0.21–0.32)2040.66***(0.57–0.75)8492.73***(2.56–2.92)7032.26***(2.10–2.43)680.22***(0.17–0.28)19056.13***(5.87–6.40) 2646612420.38(0.33–0.43)1270.20(0.17–0.24)14422.25(2.13–2.36)8031.25(1.17–1.34)400.06(0.05–0.08)26544.14(3.98–4.29) 100days1291446162.12***(1.96–2.29)16275.60***(5.34–5.87)14555.00***(4.76–5.26)8442.90***(2.71–3.10)1450.50***(0.42–0.59)468716.12***(15.70–16.55) 26116417832.96(2.83–3.10)15012.49(2.37–2.61)17222.85(2.72–2.98)10741.78(1.67–1.88)920.15(0.12–0.19)617210.23(9.99–10.47) 1year12427523629.85***(9.47–10.23)12545.21***(4.94–5.50)15506.45***(6.14–6.76)7473.11°(2.90–3.33)2040.85***(0.74–0.97)611725.47°(24.92–26.02) 252756639213.18(12.88–13.48)20894.28(4.10–4.46)21194.34(4.17–4.53)13582.79(2.65–2.94)2630.54(0.48–0.61)1222125.14(24.75–25.52) 5years117630183110.71***(10.25–11.18)5042.95***(2.71–3.22)4962.89§(2.65–3.15)4322.54***(2.32–2.79)1761.04°(0.89–1.20)343920.14***(19.54–20.74) 233714371413.26(12.85–13.67)10553.85(3.62–4.08)8082.85(2.66–3.05)9213.45(3.23–3.68)2370.90(0.79–1.03)673524.31(23.79–24.83) Overallallstudypatients131128527816.29***(15.87–16.71)376311.75***(11.39–12.11)447514.20***(13.82–14.60)33808.93***(8.61–9.25)9411.96***(1.81–2.13)1783753.13***(52.57–53.70) 2646611237123.10(22.73–23.47)48988.74(8.50–8.99)617810.56(10.30–10.81)44167.58(7.35–7.81)7231.26(1.16–1.36)2858651.23(50.79–51.68) Timeperiod:referstothetimeperiodfromdayoftransplant(seemethodsfordetails) Cohort:referstothetwotimeperiods1980–2001(cohort1)or2002–2015(cohort2) Totalatentry:referstothenumberofpatientsatrisk,atentrytotherespectivetimeperiod, e.g.,day0for30daysperiod,day30for100daysperiod,day100for1yearperiod,and1yearfor5yearsperiod. ND:numberofdeathsduringtherespectivetimeperiod CumInc+CI:CumulativeIncidence,and95%confidenceintervals.ForfulldetailsseesupplementaryTables5and7. StatisticalsignificanceinCumIncbetweencohort1and2:§=n.s.;°=<0.05;*=<0.01;**=<0.001;***=<0.0001(i.e.riskofdeathfromrespectivecausedecreased/increasedfromcohort 1tocohort2) Table2BCausesofdeathsin114′491patientswithleukemiaandHSCTbetween1980and2015,andcumulativeincidencesofdeathsdependingonpatientcohortandtimeperiodafter transplant.Patientsafterauto-HSCT TimeperiodCohortTotalatentryRelapseInfectionsOthercausesUnknownTotal NDCumInc+CINDCumInc+CINDCumInc+CINDCumInc+CINDCumInc+CI 30days111869360.31§(0.22–0.42)1981.68**(1.46–1.93)1401.19***(1.01–1.40)130.11§(0.06–0.19)3873.29***(2.98–3.63) 26833230.34(0.23–0.51)731.09(0.86–1.36)390.58(0.42–0.79)80.12(0.06–0.23)1432.14(1.81–2.50) 100days1113363533.14***(2.83–3.48)2312.05***(1.80–2.32)2091.86***(1.62–2.12)330.29°(0.21–0.41)8267.34***(6.87–7.83) 264591332.12(1.79–2.50)470.74(0.55–0.98)440.70(0.51–0.93)70.11(0.05–0.22)2313.67(3.23–4.16) 1year110344207320.52**(19.74–21.32)3593.54***(3.20–3.92)2672.63*(2.33–2.96)790.78§(0.62–0.97)277827.48***(26.61–28.35) 2585397418.31(17.28–19.37)1011.89(1.55–2.28)1142.12(1.76–2.54)390.74(0.53–1.00)122823.06(21.93–24.21) 5years17166161623.51***(22.51–24.52)1992.90***(2.52–3.31)2173.18§(2.79–3.62)1011.51§(1.23–1.82)213331.09***(29.99–32.20) 2377358918.04(16.72–19.40)521.59(1.20–2.07)1163.80(3.16–4.53)351.14(0.81–1.57)79224.57(23.07–26.10) Overallallstudypatients111869434937.01***(36.10–37.92)10118.72***(8.21–9.26)10187.41***(6.94–7.91)3552.07§(1.82–2.35)673355.22***(54.28–56.15) 26833177832.77(31.47–34.08)2774.75(4.21–5.33)3566.02(5.38–6.71)1011.75(1.41–2.15)251245.29(43.88–46.69) Timeperiod:referstothetimeperiodfromdayoftransplant(seemethodsfordetails) Cohort:referstothetwotimeperiods1980–2001(cohort1)or2002–2015(cohort2) Totalatentry:referstothenumberofpatientsatrisk,atentrytotherespectivetimeperiod, e.g.,day0for30daysperiod,day30for100daysperiod,day100for1yearperiod,and1yearfor5yearsperiod. ND:numberofdeathsduringtherespectivetimeperiod CumInc+CI:CumulativeIncidence,and95%confidenceintervals.ForfulldetailsseesupplementaryTables5and7. StatisticalsignificanceinCumIncbetweencohort1and2:§=n.s.;°=<0.05;*=<0.01;**=<0.001;***=<0.0001(i.e.riskofdeathfromrespectivecausedecreased/increasedfromcohort 1tocohort2)
viral, 1% of parasitic, and 5.2% of mixed origin (Fig. 3, Fig. S1B). Mortality from mixed/unknown infections increased from cohort 1 to cohort 2 in the very early phase (+30d: 1.35; 95%CI 1.25–1.47 vs 1.54; 95%CI 1.45–1.63).
Mortality from bacterial, viral, fungal and parasitic infec- tions decreased in very early, early, and intermediate phases (Fig.3, Fig. S1B). In the late phase, mortality from bacterial and fungal infections decreased, while mortality from viral, mixed or unknown infectious etiology did not change (Table S1A). The pattern of infectious deaths, including bacterial, viral, fungal and parasitic infections was similar for allo- and auto-HSCT, but with a distinct and constantly
lower CumInc for all types of infections at all phases after HSCT for auto-HSCT (Tables S1BC, Tables S2-S6).
Factors associated with death from infections
Factors associated with death from infection after HSCT related to patient, disease, donor-type, stem cell source, year of transplant and center specific macro- or micro-economic properties. Their impact varied significantly depending on main donor type (autologous vs. allogeneic) and the phase after transplant (Table 3A and Table 3B, Fig. S2AB).
Increasing age of the patient, advanced disease stage, donor
0.10
0.08
0.06
0.04
0.02
0.00
0 5 10 15 20 25 30 35
Days from HSCT
0.20
0.16
0.12
0.08
0.04
0.00
0 10 20 30 40 50 60 70 80 90 100 110
Days from HSCT
0.40 0.36 0.32 0.28 0.24 0.20 0.16 0.12 0.08 0.04 0.00
0 40 80 120 160 200 240 280 320 360 400
Days from HSCT Months from HSCT
0.30 0.27 0.24 0.21 0.18 0.15 0.12 0.09 0.06 0.03 0.00
0 6 12 18 24 30 36 42 48 54 60 66
Cumulative incidenceCumulative incidence Cumulative incidenceCumulative incidence
Patients alive at day 0 Number of death at day 30 in:
Relapse GvHD Infection Other causes Unknown causes
42997 (100%) 1980-2001
117 204 1047 843
81 48
842 1515 127 265 2002-2015
71494 (100%) Patients alive at day 30
Number of death at day 100 in:
Relapse GvHD Infection Other causes Unknown causes
34967 (81.3%) 1980-2001
969 1627 1686 1053
178 99
1118 1769 1501 1916 2002-2015 61220 (85.6%)
Patients alive at 1 year Number of death at 5y in:
Relapse GvHD Infection Other causes Unknown causes
3447 504 695 649
277 272
1037 860 1055 4303 2002-2015 37487 (52.4%) 24796 (57.7%)
1980-2001 Patients alive at day 100
Number of death at 1 year in:
Relapse GvHD Infection Other causes
Unknown causes 283 302
1472 1014
1909 2220
2089 1254
4435 7366
2002-2015 1980-2001
34619 (80.5%) 58609 (82.0%)
1980-2001 2002-2015 Relapse
Relapse+GvHD Relapse+GvHD+infection Relapse+GvHD+infection+other causes Relapse+GvHD+infection+other causes+unknown causes
a
c
b
d
Fig. 1 Cumulative incidences of mortality after HSCT over four post- transplant phases and from cohort 1 to cohort 2. The stacked curves for the four post-transplant phases for the two cohorts combined in
landmark analysis are presented: a 30-day mortality; b 100-day mor- tality (for patients alive at day 30); c 1-year mortality (for patients alive at day 100); d 5-year mortality (for patients alive at 1 year)
16 14 12 10 8 6 4 2 0
Cumulative incidence [%]
14 12 10 8 6 4 2 0
25
20
15
10
5
0 Relapse 1
Relapse 2 GvHD 1 GvHD 2 Infection 1 Infection 2 Other causes 1 Other causes 2 Unknown 1 Unknown 2
Relapse 1 Relapse 2 GvHD 1 GvHD 2 Infection 1 Infection 2 Other causes 1 Other causes 2 Unknown 1 Unknown 2
Relapse 1 Relapse 2 Infection 1 Infection 2 Other causes 1 Other causes 2 Unknown 1 Unknown 2
a b c
30 da ys
100 da ys
1 year 5 y
ears
30 da ys
100 da ys
1 year 5 y
ears
30 da ys
100 da ys
1 year 5 y
ears
Fig. 2 Main causes of death and of infectious deaths after HSCT. Main cause of death (in %)by post-transplant phase and by cohorts 1 and 2 (1= cohort 1980–2001; 2 = cohort 2002–2015): a all patients; b allo- HSCT patients; c auto-HSCT patients. Cumulative incidences of
mortality for the respective cause of death during the 4 post-transplant time periods, day 0 to day 30, day 30 to day 100, day 100 to 1 year, and 1 year to 5 years (see methods section for details), are shown
type, and second or later transplant were associated with increased risk of infectious death in all phases and for all donor types. Patient sex showed no associations at all.
Peripheral blood as stem cell source was associated with less infectious deaths in all post-transplant phases after auto- logous HSCT; it was associated with more infectious deaths after allogeneic HSCT in the late phase, reflecting the higher probability of chronic GvHD with peripheral blood. This same association with GvHD in the late phase is reflected by the higher rate of deaths from infections in the HY+ donor recipient combinations (Table3A and Table3B, Fig. S2AB).
Of note, country specific macro-economic factors, GNI/
capita and geographic region, were associated only during the very early and early post-transplant phase; the same applied to centre specific micro-economic factors. Centres with more than 20 years of disease specific transplant experience had significantly less infectious death in the early and intermediate post-transplant phases. No significant association could be documented between death from infections and JACIE accreditation status, in contrast to the association with overall mortality.
Discussion
The results of this comprehensive study are clear: the Eur- opean transplant teams have successfully managed to reduce all-cause mortality after autologous HSCT at all post-transplant time phases. In allogeneic HSCT, they were successful in reducing deaths from GVHD, infections and other causes in the very early and early post-transplant time phases, despite an increase in the patient pre-transplant risk profile. In contrast, data did not show a reduction of death from relapse after allogeneic HSCT, and no reduced mor- tality in the late post-transplant phase. The latter observation is of concern, but indicates areas for improvements.
The analysis confirmed well established disease, patient, donor, transplant and center-related risk factors for death from all causes and from infection after transplant [1,2,21].
Novel is the observation that not all factors are equally relevant during all post-transplant time phases. Advanced disease stage at time of transplant remains associated with increased risk of mortality from all causes throughout the whole post-transplant phase, and so is increasing age of the recipient, with the exception of the very early phase where other factors dominate. During all post-transplant phases, allogenicity dominates. Of note, the HY+effect adds bearing on mortality primarily after day 100; the early beneficial effect of peripheral blood stem cells reverts to a detrimental effect beyond 1 year. As observed earlier, accreditation status of the center is associated with mortality of the patients and with overall improvement over calendar year time [22].
The same risk factors were associated with death from infections. Late disease stage was in all post-transplant phases associated with more infectious deaths. Increasing age contributed to risk of death from infection in a hier- archical effect by decade. Of interest, despite an increase in age in cohort 2, deaths from infections were still reduced, reflecting the possible benefit of better management of infectious complications, through novel diagnostic methods, drugs and guidelines [9–11,23–25]. Cord blood as a stem cell source was associated with a higher rate of infectious deaths in thefirst three post-transplant phases, but no longer after 1 year. Peripheral blood as a stem cell source was associated with a lower rate of deaths in the first three phases, not in the last. These results might have been influenced by an additional, indirect late GVHD effect of peripheral blood stem cells. This is supported by the increased risk of infectious deaths in HY+ donor recipient combinations. Of note, disease specific center experience in years was strongly associated with reduced infectious deaths in the early post-transplant phase [22].
3
2.5
2
1.5
1
0.5
0
Cumulative incidence [%]
30 da ys
100 da ys
1 year 5 y
ears
30 da ys
100 da ys
1 year 5 y
ears
30 da ys
100 da ys
1 year 5 y
ears 1.8
1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 4
3.5 3 2.5 2 1.5 1 0.5 0 Bacterial 1 Bacterial 2 Viral 1 Viral 2 Fungal 1 Fungal 2 Parasitic 1 Parasitic 2 Mixed 1 Mixed 2 Unknown 1 Unknown 2
Bacterial 1 Bacterial 2 Viral 1 Viral 2 Fungal 1 Fungal 2 Parasitic 1 Parasitic 2 Mixed 1 Mixed 2 Unknown 1 Unknown 2
Bacterial 1 Bacterial 2 Viral 1 Viral 2 Fungal 1 Fungal 2 Parasitic 1 Parasitic 2 Mixed 1 Mixed 2 Unknown 1 Unknown 2
a b c
Fig. 3 Main causes of death and of infectious deaths after HSCT.
Causes of infectious deaths by post-transplant phase. Changes over time of causes of infectious deaths (in %) after HSCT for leukemia by post-transplant phase (1= cohort 1980–2001; 2 = cohort 2002–2015):
a all patients; b allo-HSCT patients; c auto-HSCT patients.
Cumulative incidences of mortality for the respective cause of death during the 4 post-transplant time periods, day 0 to day 30, day 30 to day 100, day 100 to 1 year, and 1 year to 5 years (see methods section for details), are shown
There are major caveats in this study. It looks at very heterogeneous data over a long time period with many changes in disease indications, choice of donor type, stem cell source. over calendar year time. Data were derived from a multitude of centers from many countries with different micro- and macroeconomic backgrounds. Some data, such as cytogenetic profiles were not in the data set. Some decisions had to be arbitrary, such as the use of economic factors as of the year 2016. Centers had varying attitudes regarding data collection, and potentially different inter- pretations of“cause of death”. Simply, we used the data as they were reported to the database, and we accepted the information as given by the center, including the high rate
of deaths and infectious deaths of“unknown” origin. Still, the consistency of the findings in the four post-transplant phases, and the confirmation of key risk factor elements are strong arguments that the data are valid. They were as well in line with our pre-set hypotheses, that factors associated with overall mortality and from infections would differ depending on the post-transplant phase. This was the case, but is of concern. Mortality was reduced early post-trans- plant, but increased in the late phase after allogeneic HSCT.
Hence, improvements were more rapidly visible than dete- riorations; the increase in late mortality years after the transplant might not be recognized to the same extent, with patients frequently at distance from the center. Lethal Table 3A Factors associated with death from infection after HSCT in multivariate analysis. Factors associated with death from infection after HSCT in all patients
Parameter Variables
s r a e y 5 r
a e y 1 s
y a d 0 0 1 s
y a d 0 3
1 + r a e y t a e v i l a s t n e i t a P 0
0 1 + y a d t a e v i l a s t n e i t a P 0
3 + y a d t a e v i l a s t n e i t a P s
t n e i t a p l l A
HR 95% HR CI p p* HR 95% HR CI p p* HR 95% HR CI p p* HR 95% HR CI p p*
Year of HSCT
1980-2001 1.503 1.349 1.676 <0.0001
<0.0001
1.935 1.764 2.122
<0.0001
1.711 1.572 1.862 <0.0001
<0.0001
1.380 1.229 1.550 <0.0001
<0.0001 0
0 0 . 1 0
0 0 . 1 0
0 0 . 1 0
0 0 . 1 5
1 0 2 - 2 0 0 2
Patient age
0 0 0 . 1 c
i r t a i d e P
<0.0001
1.000
<0.0001
1.000
<0.0001
1.000
<0.0001 Adult 2.371 2.081 2.701 <0.0001 1.529 1.384 1.690 1.925 1.743 2.127 <0.0001 2.171 1.840 2.560 <0.0001
Patient sex
e l a M
ns
1.000
0.0246 ns ns
2 7 1 . 1 1 1 0 . 1 9 8 0 . 1 e
l a m e F
Underlying disease
ALL 1.914 1.671 2.192 <0.0001
<0.0001
1.126 1.015 1.250 0.0257
0.0012
1.262 1.144 1.392 <.0001
<0.0001
1.593 1.353 1.875 <.0001
<0.0001 AML 1.550 1.367 1.757 <0.0001 0.965 0.879 1.059 0.4525 1.157 1.061 1.261 0.0010 1.342 1.163 1.549 <.0001
0 0 0 . 1 0
0 0 . 1 0
0 0 . 1 0
0 0 . 1 L
M C
Stage class early 1.000
<0.0001 1.000
<0.0001 1.000
<0.0001 1.000
<0.0001 late 2.159 1.983 2.350 <0.0001 1.441 1.342 1.547 1.424 1.334 1.520 <0.0001 1.408 1.262 1.571 <0.0001
Stem cell source
0 0 0 . 1 M
B
<0.0001
1.000
<0.0001
1.000
<0.0001 ns
CB 1.974 1.572 2.480
<0.0001 1.743 1.450 2.096 <.0001 1.355 1.107 1.658 0.0032
PB 0.930 0.846 1.022 0.1303 0.787 0.726 0.854 <.0001 0.865 0.804 0.931 0.0001
Type of HSCT
0 0 0 . 1 s
u o g o l o t u A
<0.0001
1.000
<0.0001
1.000
<0.0001
1.000
<0.0001 HLA-idsibHY+/matched family HY+ 1.541 1.295 1.835 <0.0001 1.856 1.567 2.199 <.0001 2.020 1.777 2.297 <.0001 1.244 1.026 1.508 0.0265 HLA-idsibHY-/matched family HY- 1.390 1.203 1.607 <0.0001 1.949 1.699 2.236 <.0001 1.409 1.259 1.577 <.0001 0.939 0.801 1.102 0.4414
matched unrelated HY+ 2.202 1.787 2.713 <0.0001 3.588 2.960 4.349 <.0001 3.060 2.607 3.592 <.0001 1.718 1.332 2.217 <.0001
matched unrelated HY- 1.970 1.688 2.298 <0.0001 3.505 3.037 4.044 <.0001 2.447 2.171 2.758 <.0001 1.445 1.217 1.716 <.0001
mismatched family 3.452 2.906 4.100 <0.0001
6.167 5.253 7.241 <0.0001 4.514 3.909 5.213 <.0001 2.138 1.663 2.748 <.0001 mismatched unrelated 1.884 1.491 2.381 <0.0001 4.147 3.428 5.017 <0.0001 3.380 2.851 4.008 <.0001 1.480 1.103 1.985 0.0089 syngeneic 1.156 0.595 2.249 0.6684 1.242 0.660 2.335 0.5015 0.713 0.369 1.381 0.3161 1.122 0.577 2.184 0.7339
Number of HSCT
0 0 0 . 1 t
s r i F
<0.0001
1.000
<0.0001
1.000
0.0100
1.000
0.0004 Second or more 2.274 2.056 2.515 <0.0001 1.864 1.688 2.059 <0.0001 1.158 1.036 1.294 0.0100 1.392 1.161 1.669 0.0004
Geographic region
0 0 0 . 1 t
s e w - h t r o n
<0.0001 ns ns ns
east 1.442 1.248 1.667 <0.0001
south 1.153 1.052 1.265 0.0024
GNI
0 0 0 . 1 e
m o c n i h g i h
0.0003
1.000
0.0185 ns ns
upper/lower middle income 1.310 1.130 1.519 0.0003 1.185 1.029 1.364 0.0185
JACIE accreditation 2016
d e r i p x E / d e t i d e r c c A
ns ns
1.000
0.0275 ns
Withdrawn/not accredited 0.923 0.860 0.991 0.0275
Centre experience
0 - 4 1.564 1.327 1.844 <0.0001
<0.0001
1.361 1.178 1.573 <.0001
<0.0001
1.294 1.136 1.474 0.0001
<0.0001 ns 5-19 1.351 1.226 1.489 <0.0001 1.316 1.212 1.428 <.0001 1.138 1.057 1.225 0.0006
0 0 0 . 1 0
0 0 . 1 0
0 0 . 1 +
0 2
Centre size was defined for each transplant by the number of transplants performed in the center for the main disease of the patient in the year of the transplant (0–4, 5–19, 20 + transplants). Centre experience in years was defined by the number of years that the center had performed transplants until the year of the transplant of the patient (0–4, 5–19, 20 + years of program). Country macroeconomic status was defined by gross national income (GNI/capita) in 2016 (high income, upper middle income, lower middle income) (source:www.worldbank.org). Geographical regions were defined as: north-western (Austria, Belgium, Denmark, Finland, France, Germany, Luxembourg, Netherlands, Norway, Sweden, Switzerland, UK), eastern (Bulgaria, Croatia, Czech Republic, Hungary, Lithuania, Macedonia, Poland, Romania, Russia, Slovakia) and southern (Cyprus, Greece, Israel, Italy, Portugal, Spain, Turkey, and other EBMT countries). JACIE accreditation status (accredited, expired, withdrawn and not accredited) in 2016 was used. HR > 2.0 is highlighted in orange; HR > 1.5 is highlighted in yellow.